Genome-Wide Association Study of Anorexia Nervosa
Anorexia Nervosa Anorexia nervosa is a psychiatric disorder present in ~1% of the global population. The disorder is characterized by a fear of weight gain, dangerously low body weight, and a seeming unresponsiveness to the severity of the illness; patients intentionally strive to maintain a low BMI. Typically, females aged 15 to 19 years old are affected, but both females and males of all ages may develop eating disorder tendencies. Anorexia nervosa has one of the highest mortality rates of all psychiatric disorders, as well as limited treatment options. While the disorder may develop ‘spontaneously’ in patients, it has been shown to be highly heritable throughout families; multiple twin studies have proven the heritability rate to be anywhere from 33% to 84%. While anorexia nervosa is the general diagnosis given, there are two distinctly different subtypes that may affect patients: the restrictive subtype, and the binge-purge subtype (1). Previous Genome-Wide Association Studies Two former, smaller genome-wide association studies analyzing the genomics of anorexia nervosa have been performed. The first GWAS investigated the SNP rs2048332 on chromosome 1, but came to no significant conclusions. The second GWAS suggested an association between cholesterol metabolism and the role of the EPHX2 ''gene influencing anorexia nervosa predisposition (1). The Wellcome Trust Case Control Consortium 3 GWAS The WTCCC3 GWAS is the largest anorexia nervosa GWAS performed to date. The parameters of the study included: * 15 data sets, comprising * 2,907 anorexia nervosa cases * 14,860 control cases (all of which were ancestrally matched to the anorexia nervosa cases) * All participants were females Participants were not excluded based on: age, ethnicity, previous bulimia nervosa tendencies, or amenorrhea. All participants met the DSM-IV criteria for anorexia nervosa diagnosis. Participants were excluded based on: other mental disabilities (mental retardation, psychotic disorders, other psychological disorders causing weight loss). Each individual anorexia nervosa case was genotyped separately, according to data set group; an Illumina 660W-Quad array chip was used to genotype individual cases. The information from all the data sets was combined to create a larger pool for analysis. In total, 96 SNPs in 66 regions showed some evidence of association; 95 of these SNPs were autosomal, while 1 SNP was found on the X chromosome. Researchers decided upon 76 SNPs to prioritize and track. They investigated evidence relating these results to the SNP association results of former anorexia nervosa studies. Researchers compared: * 9 SNPs with nominal evidence association to anorexia nervosa * 14 SNPs associated with eating disorder related behaviors, symptoms, and personality traits * 89 SNPs associated with obesity and BMI * 15 SNPs associated with morbid obesity Researchers also investigated evidence relating SNPs associated with mental disorders (including ADHD, bipolar disorder, major depressive disorder, and schizophrenia) to anorexia nervosa. The goal was to determine which SNPs were associated with anorexia nervosa in general, which SNPs were associated with the restrictive anorexia nervosa subtype, and which SNPs were associated with the binge-purge anorexia nervosa subtype. Results Of the 1,185,599 SNPs that met the qualifications to analyze, 287 SNPs, or variants of these SNPs, showed evidence for association. Researchers aspired to determine a distinct difference between SNPs relating to the restrictive subtype of the disorder and the binge-purge subtype (1). In general, two notable variants associated with the anorexia nervosa genotype were discovered: * rs9839776 in the ''SOX2OT ''(SOX2 overlapping transcript) gene, located on chromosome 3, position 181593779 (2) * rs17030795 in the ''PPP3CA (protein phosphatase 3, catalytic subunit, alpha isozyme) gene, located on chromosome 4, position 101126919 (3) Two notable variants associated with the anorexia nervosa genotype were discovered in European populations only: * rs1523921, found between the CUL3 (cullin 3) gene and the FAM124B (family with sequence similarity 124B) gene, located on chromosome 2, position 224444261 (4) * rs1886797, found 18kb from the SPATA13 ''(spermatogenesis associated 13) gene, located on chromosome 13, position 23961849 (5) Two notable variants were discovered to be associated with the restrictive anorexia nervosa subtype: * rs1523921 located on chromosome 2, position 224444261 (6) * rs10777211, found 333kb from the ''ATP2B1 (ATPase, calcium transporting, plasma membrane 1) gene, located on chromosome 12, position 89932155 (7) One notable variant was discovered to be associated with the binge-purge anorexia nervosa subtype: * rs9839776 in the SOX2OT (SOX2 overlapping transcript) gene, located on chromosome 3, position 181593779 (2) Of the results gathered, out of 11 SNPs previously reported to be associated with anorexia nervosa, 9 SNPs were confirmed in this study; out of 14 SNPs previously reported to be associated with eating disorder related behaviors, symptoms, and personality traits, 12 SNPs were confirmed in this study. Researchers did not find evidence linking 89 SNPs associated with obesity to the 76 SNPs associated with anorexia nervosa. In addition, they did not find any evidence linking SNPs associated with ADHD, bipolar disorder, major depressive disorder, or schizophrenia to SNPs associated with anorexia nervosa (1). The general conclusions researchers came to were how a larger sample size would have yielded stronger results. A larger sample size has the potential to allow researchers to distinctively determine the genomic differences between those who suffer from restrictive anorexia nervosa versus those with binge-purge anorexia nervosa (1). References 1) Boraska V, Franklin CS, Floyd JAB, et. al. A genome-wide association study of anorexia nervosa. Molec Psych. 2014; 19: 1085-1094. doi: 10.1038/mp.2013.187. 2) rs9839776. National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/snp/?term=rs9839776. Updated 2014. Accessed November 2, 2014. 3) rs17030795. National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/snp/?term=rs17030795. Updated 2014. Accessed November 2, 2014. 4) rs1523921. National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/snp/?term=rs1523921. Updated 2014. Accessed November 2, 2014. 5) rs1886797. National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/snp/?term=rs1886797. Updated 2014. Accessed November 2, 2014. 6) rs1523921. National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/snp/?term=rs1523921. Updated 2014. Accessed November 2, 2014. 7) rs10777211. National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/snp/?term=rs10777211. Updated 2014. Accessed November 2, 2014.